The long range goal is to provide intervention to delay or prevent cognitive decline associated with unsuccessful aging, in order to improve the health and well-being of older Americans. The incidence of Alzheimer's disease (AD) is projected to increase dramatically in the next several decades with the greatest prevalence in women. Loss of synapses contributes to memory impairment during 'normal'aging and during the early stages of the AD. Synaptic loss may be reversible by treatments initiated during middle-age. Estrogen (E2) promotes synaptogenesis and facilitates memory. As such, E2 treatment could have a major impact on public health. However, the efficacy of E2 treatment is greatly reduced or nonexistent if therapy is set in motion several years after the onset of menopause. The effectiveness of E2 treatment, limited to middle-age, suggest that there is a temporally limited therapeutic window. Mounting evidence indicate that the level of estrogen receptor (ER) expression and ER polymorphisms are contributing factors for a variety of hormone sensitive diseases, including cognitive decline. We hypothesize that differential expression of ERalpha and ERbeta contribute to the etiology of 1) age-related memory deficits, 2) loss of E2 mediated synaptogenesis, and 3) the closing of the E2 therapeutic window. Our working hypothesis is that ERalpha is the predominate receptor and ERbeta can have weaker effects or act as an inhibitor of ERalpha activity. Specific aim 1 will use ERalpha and ERbeta knockouts mice and systematically performing behavioral and molecular assays to test the hypothesis that ERalpha is the predominate receptor for maintaining hippocampal function when endogenous E2 levels decline during middle-age. Thus, these experiments will determine whether the expression of ERalpha or ERbeta is important for the etiology of age-related memory decline. Specific aim 2 will employ viral delivery of ERalpha or ERbeta vectors to the hippocampus of young, middle-age, and aged rats, and will use behavioral, electrophysiological, and molecular assays to test the hypothesis that increasing ERalpha expression rejuvenates hippocampal function. These experiments will determine whether increasing the level of ERalpha or ERbeta expression is important for age-related declines in memory, E2-induced synaptogenesis, and closing of the E2 therapeutic window. Specific aim 3 will employ viral vector mediated delivery of small interfering RNA for the down regulation of target genes, ERalpha or ERbeta, and will test the hypothesis that decreased ERalpha expression contributes to hippocampal aging and ERbeta silencing can ameliorate impairments in memory and E2-induced synaptogenesis during aging. ER knockout mice and viral vector gene delivery provide novel approaches to test the hypothesis that ER expression is a contributing factor for hippocampal aging. The results of our experiments may provide the groundwork for future development of ER gene therapies to slow or prevent cognitive decline associated with aging and age- related diseases.